Mouse liver responds to chronic administration of carbon tetrachloride (CCl4) with repetitive sequences of parenchymal cell necrosis and regeneration. A high frequency of liver tumors composed of non-malignant adenomatous tissue represents the ultimate adaptative adjustment to such long-term chemical injury. Liver DNA damage follows an acute dose of CCl4 and in both acute and chronic exposure to CCl4 there is a modest level of hydroxyurea-insensitive liver DNA synthesis. Ultracentrifugation of bromodeoxyuridine-labelled DNA in either alkaline CsCl or neutral NaI-ethidium bromide demonstrated DNA repair synthesis only inconsistently. More conclusive evidence has been obtained for DNA-protein cross linking suggesting that cytoplasmic nucleases, liberated by CCl4, damage chromatin DNA and that much of the reconstitution of the damaged DNA takes place by recombination. Liver DNA-protein cross linking in CCl4-treated mice will be pursued using density gradient ultracentrifugation and adapting a filter binding assay. Determinations also will be made of any possible adducts formed between 14C-CCl4 and liver DNA. Preliminary experiments indicate some significant changes in template specificity of DNA dependent RNA polymerase activity in CCl4-treated mice and these experiments will be continued. Comparable experiments will be performed with chromatin and DNA from livers of mice treated chronically with phenobarbital. DNA-protein cross linking and nuclear polymerase activity will be studied in tumors induced by chronic CCl4 treatment and by chronic treatment with phenobarbital.